Models of intrinsic regulation of blood flow involving tissue adenosine have typically considered the influence of the metabolites, flow, pressure, and vascular communication. One consistent problem with the study of metabolites is that adenosine metabolism is consistently found to be a critical player, but in-vivo findings of adenosine concentration don't mesh with in-vitro responses. Our new data reveal that adenosine generates dilations in the vascular network that appear to be due to activation of receptors in the tissue. This mode of adenosine initiated network dilation is unique from a direct effect of adenosine on the vessel wall, and much more potent. The dilation does not appear to follow any specific blood flow path, its magnitude depends on the amount of stimulated tissue, and it cannot be explained by diffusion, veno-arteriolar transfer, or flow dependent changes. In addition, unlike the dilatory response caused by direct application of adenosine onto the vessel, the network dilation is not dependent on nitric oxide. This has raised a couple of fundamental questions: 1) can this mechanism cause maximal vasodilation? 2) is neural conduction a component of the network response? 3) where are the adenosine receptors that initiate the response? 4) has endothelium been ruled out as the cell type initiaitng the network response? and 5) does it play a role in ischemic preconsitioning? We know KATP channels are critical to initiate the response. Using a KATP dominant negative construct and cell-type specific promoters we will knock down intrinsic KATP channel function as a tool to understand the mechanisms. These new data on adenosine will begin to shed light on conflicting data that is part of the adenosine literature. Quantifying the vascular communication and network responses caused by adenosine will give us a better understanding of basic mechanisms of vascular responses and help us better understand the physiology of brain and cardiac ischemic preconditioning, as well as the microcirculatory disorders associated with sepsis.